Intermediates for benzindenes

ABSTRACT

Benz(e)indene derivatives and intermediates therefore have been prepared by various processes starting from hexahydroindane derivatives. The benz(e)indene end products belong to a known class of compounds and are useful as intermediates in the synthesis of steroidal compounds.

United States Patent 11 1 Furst et al.

[ Dec. 16, 1975 INTERMEDIATES FOR BENZINDENES [75] Inventors: AndorFurst, Basel; Paul Buchschacher, Arlesheim; Dieter Kagi, Allschwil;Werner Meier, Bottmingen; Marcel Mi'lller, Frenkendorf; Erich Widmer,Munchenstein, all of Switzerland [73] Assignee: l-loffmann-La RocheInc., Nutley,

22 Filed: Mar. 27, 1974 21 Appl. No: 455,084

Related US. Application Data [62] Division Of Ser. No. 256.555. May 24.1972. Pat. No.

[30] Foreign Application Priority Data Nov. 19. 1968 Switzerland17224/68 [52] US. Cl. 260/3403 [51] Int. Cl. C07D 317/30 [58] Field ofSearch 260/3409, 340.7, 338

[ 5 7 ABSTRACT Benz[e]indene derivatives and intermediates thereforehave been prepared by various processes starting from hexahydroindanederivatives. The benzlelindene end products belong to a known class ofcompounds and are useful as intermediates in the synthesis of steroidalcompounds.

5 Claims, No Drawings INTERMEDIATES FOR BENZINDENES RELATED APPLICATIONSBRIEF SUMMARY OF THE INVENTION The invention relates to processes forpreparing com pounds of the formula wherein R is hydrogen or a C, alkylgroup and D represents one of the residues wherein R is an acetyl group,which may be ketalized, a l-hydroxyethyl or a l-acyloxyethyl group.

In another aspect, the invention relates to novel intermediates.

DETAILED DESCRIPTION OF THE INVENTION The present invention is concernedwith a process for the manufacture of compounds of the general formulawherein R is hydrogen or a C alkyl group and D represents one of theresidues wherein R is an acetyl group, which may be ketalised, al-hydroxyethyl or a l-acyloxyethyl group.

The process in accordance with the invention comprises the cyclisationof a compound of the general formula ll R-- 0-05;

wherein X is oxygen or a C alkylidene group; R when X represents oxygen,is a group -CH R and R has the above meaning, and, when X represents a Calkylidene group, is a hydroxy or lower alkoxy group or halogen, and Dhas the same meaning as above. A C alkyl group represented in theforegoing formulae by the symbol R can be straight-chain or branched.Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl orbutyl and isomers thereof. R is preferably hydrogen or methyl. Examplesof ketalised acetyl groups represented by the symbol R are l,l-(loweralkylenedioxy)-ethyl groups, especially the l,l-ethylenedioxyethylgroup. Examples of l-acyloxyethyl groups are l-(lower alkanoyloxy)-ethylgroups such as l-acetoxyethyl; or l-hydroxyethyl groups esterified witharomatic carboxylic acids such as l-benzoyloxy-ethyl. A C,.,, alkylidenegroup represented by the symbol X is preferably the methylene orethylidene group. Further examples of such groups are propylidene,butylidene, 2-methylpropylidene or pentylidene.

A loweralkoxy group represented by the symbol R preferably contains 1-4C-atoms; examples of such groups are especially methoxy and ethoxy. Ahalogen represented by R is preferably chlorine.

The cyclisation of a compound of formula II to a compound of formula Iin accordance with the invention can be effected by treatment withalkaline or acidic condensation agents. Suitable alkaline condensationagents are alkali metal hydroxide solutions such as aqueous-alcoholic(especially aqueous-methanolic) caustic potash or organic bases such aspyrrolidine. Acidic condensation agents are organic acids, mineral acidsand Lewis acids. As organic acids there can be used, for example,carboxylic acids such as acetic acid, or p-toluenesulfonic acid, and,when in a compound of formula II X is alkylidene, an organic acid inadmixture wih an organic acid anhydride, especially acetic anhydride.Examples of suitable mineral acids are sulfuric acid, hydro halic acidsor phosphoric acids (especially pounds of the general formula II.

a. According to one embodiment of this invention compounds of formula IIwith X being oxygen can be prepared by reduction of a compound offormula D III 5 c HOOC--CH/ 2 wherein D has the above meaning, to acompound of formula H HOOC -cn 2 i wherein D represents a residue or v Oy lb I 0 wherein R is a ketalised acetyl group, a l-hydroxyethyl 40 or al-acyloxy-ethyl group, cyclisation of a compound of formula IV to acompound of formula V pound of formula ketalization of a keto groupwhich may be present in the residue D, reaction of a compound of formulathus obtained, wherein D has the meaning given above, with an alkylGrignard compound R Mg-halogen (R being a group CH R and R having theabove meaning), hydrolysis, and, if desired, cleavage of a ketal groupwhich may be present in the ring D.

c. According to another embodiment of this invention compounds offormula II with X being oxygen can be prepared by ketalisation of thering-located keto group and of alreto group which may be present in theresidue D of a compound of formula III, reaction of the thus obtainedketal with an alkyl-lithium compound R Li, wherein R is a group CH,'Rand R has the above meaning, and subsequent cleavage of the ketalgroup(s).

d. According to another embodiment of this invention compounds of theformula II with X being oxygen can be prepared by ketalisation of thering-located keto group and of a keto group which may be present in theresidue D of a compound of formula III, conversion into an acid amide,reaction of the acid amide thus obtained with an alkyl Grignard compoundR Mg-halogen (R representing a group CH -R and R having the abovemeaning), hydrolysis and cleavage of the ketal groups(s).

e. According to another embodiment of this invention compounds offormula II with X being oxygen can be prepared by ketalisation of thering-located keto group and of a keto group which may be present in theresidue D of a compound of formula III, transformation of the carboxygroup into a cyano group, reaction of the nitrile thus obtained with analkyl Grignard compound R Mg-halogen (R representing a group CH- -R andR having the above meaning), acidic hydrolysis and cleavage of the ketalgroup(s).

f. According to another embodiment of this invention compounds offormula II with X being oxygen can be prepared by ketalisation of thering-located keto group and of a keto group which may be present in theresidue D of a compound of formula III, transformation of the carboxygroup into a cyano group, transformation of the cyano group of thecompound thus obtained into an aldehyde group, reaction of the aldehydethus obtained with an alkyl Grignard compound R Mg-halogen (Rrepresenting a group -CH R and R having the above meaning), hydrolysis,cleavage of the ketal group(s), and subsequent oxidation.

g. According to another embodiment of this invention compounds offormula ll with X being oxygen can be prepared by ketalisation of thering-located keto group and of a keto group which may be present in theresidue D of a compound of formula III, transformation of the carboxygroup into an acid halide group, transformation of the acid halide groupof the compound thus obtained into an aldehyde group, reaction of thealdehyde with an alkyl Grignard compound R Mg-halogen (R representing agroup CH R and R having the above meaning), hydrolysis, cleavage of theketal group(s), and subsequent oxidation.

h. According to another embodiment of this invention compounds offormula II with X being oxygen can be prepared by ketalisation of thering-located keto group and of a keto group which may be present in theresidue D of a compound of formula III, transformation of the carboxygroup of the ketal into an acid halide group, reaction of the acidhalide thus obtained with a dialkyl-cadmium compound, hydrolysis andcleavage of the ketal group(s).

i. According to another embodiment of this invention compounds offormula II with X being oxygen can be prepared by esterification of thecarboxy group of a compound of formula III, ketalisation of theringlocated keto group, reduction of a keto group which may be presentin the residue D, acidic hydrolysis, cyclisation, reaction with aGrignard compound R Mghalogen (R representing a group Cl-l -R and Rhaving the above meaning), and, if desired, subsequent esterification ofa hydroxy group present in the residue D or cleavage of a ketal groupwhich may be present.

k. According to another embodiment of this invention compounds offormula ll with X being in alkylidene group and R representing a hydroxyor lower alkoxy group can be prepared by esterification of the carboxygroup of a compound of the formula VIII HOOC -cn 2 VIII 0/ H HOOC on; 2

wherein D has the above meaning, reaction of the compound thus obtainedwith an alkylidene phosphorane according to Wittig, saponification ofthe ester group to form the initially present carboxy group andtransformation of the acid into an acid halide, as well as Bleavage, ifdesired, of a ketal group present in residue The reduction of a compoundof formula lll to a compound of formula IV in accordance with embodiment(a) can be effected with complex metal hydrides such as diisobutylaluminium hydride, sodium borohydride, or with sodium and alcohol.Sodium borohydride is preferred. Condensation agents such as aceticanhydride/pyridine, sulfuric acid, polyphosphoric acid or zinc chlorideare suitable for the cyclisation of a compound of formula IV thusobtained to a compound of formula V. When using aceticanhydride/pyridine a hydroxy group in the residue D will be acctylatedsimultaneously. The reaction of a compound of formula V with an alkylGrignard or alkyl-lithium compound to give a compound of formula VI canbe carried out in a manner known per se. Chromium trioxide isparticularly suitable as an oxidising agent for the subsequent oxidationof a compound of formula VI to a compound of formula II. Cleavage of theketal group can be effected in a manner known per se in an acidicmedium.

The cyclisation of a compound of formula III to a compound of formulaVll which is to be carried out in accordance with embodiment (b) can becarried out in the same manner as the cyclisation of a compound offormula II to a compound of formula I described above. The ketalisationof a keto group which may be present in the residue D can be effected byreaction with an alcohol, especially with methanol, ethylene glycol orwith a phenol such as pyrocatechol. The reaction of a compound offormula Vll with an alkyl Grignard compound can be carried out in amanner known per se. The hydrolysis of the compound obtained can beachieved by means of ammonium chloride solution or water. The cleavageof a ketal group which may be present in the residue D can be carriedout in a known manner in an acidic medium.

According to embodiment (c), a compound of formula ill in ketalised formis converted into a compound of formula II by reaction with analkyl-lithium compound of the formula R Li. It is of advantage to workin the presence of an ether such as diethyl ether or tetrahydrofuran assolvent at elevated temperature, expediently at the reflux temperatureof the mixture. The preceding ketalisation of the ring-located ketogroup and of a keto group which may be present in the residue D as wellas the cleavage of the ketal group(s) to be carried out after thereaction can be carried out in the usual way as already described.

According to embodiment (d), an ester (e.g. the methyl ester) of acompound of formula Ill is expediently subjected to ester-aminolysisafter preceding ketalisation of the ring-located keto group and of aketo group which may be present in the residue D: The ester which is tobe reacted is allowed to react with ammonia in a solvent. expediently ina lower alkanol, advantageously at elevated temperature. The resultingacid amide is reacted with an alkyl Grignard compound R Mg-halogen. Thereaction product is subsequently hydrolysed (eg by addition of aqueousammonium chloride or water) and the ketal group is cleaved under acidicconditions.

According to embodiment (e), first the ring-located keto group and theketo group which may be present in the residue D are ketalised in aknown manner. Then the carboxy group of a compound of formula III istransformed into a cyano group, which can be done preferably withchlorosulfonyl isocyanate. The nitrile obtained is subsequently reactedwith an alkyl Grignard compound R Mg halogen in a known manner. Thenhydrolysis is carried out in acidic milieu and cleavage of the ketalgroup(s) under acidic conditions as well.

According to embodiment (f), the carboxyl group of a compound of formulaIII, after ketalisation of the ring-located keto group and of a ketogroup which may be present in the residue D is converted into a cyanogroup as described under (e). A reducing agent such as aluminiumdiisobutyl hydride can advantageously be used for the reduction of thecyano group to an aldehyde group. It is expedient to work in a solventsuch as benzene or heptane. The aldehyde group is further converted intoa secondary alcohol function by means of an alkyl Grignard compound RMg-halogen and subsequent hydrolysis of the product which is formed. Thecleavage of the ketal group(s) is effected as described under (e) inacidic milieu, cyclisation taking place simultaneously. The oxidation toa compound of formula II is suitably effected with chromium trioxide.

According to embodiment (g), the carboxyl group of a compound of formulaIII, after ketalisation of the ring-located keto group and of a ketogroup which may be present in the residue D is transformed into an acidchloride function, with reagents such as oxalyl chloride or phosphorustrichloride. It is of advantage to work under mild conditions,expediently in a weakly acidic range and somewhat below roomtemperature. A solvent such as benzene is advantageously used. The acidhalide is further converted into an aldehyde, for example, by reactionwith a reagent such as ethyleneimine in the presence of an organic base(e.g. an amine such as triethylamine) to the corresponding acid amidewhich can then be converted into the aldehyde by reduction,advantageously with lithium aluminium hydride. The furtherreaction-steps to the compound of formula III, which are formation ofsecondary alcohol, cyclisation and oxidation of the latter, is describedunder (f).

According to embodiment (h), the carboxy group of a compound of formulaIII, after ketalisation of the ring-located keto group and of a ketogroup which may be present in the residue D is firstly transformed intoan acid halide, which step has already been described under (g). Thisacid halide is then converted into a ketone by reaction with adialkyl-cadmium compound (eg dimethyl-cadmium), which reaction iscarried out expediently in a solvent such as a mixture of ether/benzene.The organo metallic complex is subsequently hydrolysed, strongly acidicconditions being avoided. Finally cleavage of the ketal groups iseffected in a known manner.

According to embodiment (i), a compound of formula II which is used asthe starting material is prepared by esterifying the carboxy group of acompound of formula III. In this case preparation of the methyl ester ispreferred which can be done by reaction of the acid with diazomethane.The ester is then ketalised selectively, which can be brought about, forexample by only allowing the ketalising agent to act until thering-located keto group has reacted. Reducing agents such as sodiumborohydride or tri-tert-butoxy lithium aluminum hydride are expedientlyused for the reduction of the keto group which may be present in theresidue D. Subsequently the ester is saponified to the freeketo-carboxylic acid under acidic conditions and cyclised to theenol-lactone by treatment with sodium acetate/acetic with simultaneousacetylation of a hydroxy group present in the residue D. Reaction with aGrignard compound R Mg-halogen, hydrolysis with water or aqueousammonium chloride and if necessary re-acetylation with aceticanhydride/pyridine yields a compound of formula II.

According to embodiment (k), a starting compound of formula II in whichX is an alkylidene group and R represents a hydroxy or alkoxy group isprepared by esterifying a compound of formula VIII. Preferably, themethyl or ethyl ester is prepared, advantageously the former, which canbe done, for example, by reaction of the acid with diazomethane. Theester is then reacted with an alkylidene phosphorane according to Wittigat elevated temperature in a solvent, such as dimethyl sulfoxide or anether, for example tetrahydrofuran or diethyl ether. Subsequently theester can be resaponified.

According to embodiment (l), a starting compound of formula II in whichX is an alkylidene group and R represents halogen is prepared byesterifying a compound of formula VIII, reacting the ester with analkylidene phosphorane according to Wittig and resaponifying the esteras already described in embodiment (k). The free acid is then convertedinto an acid halide, which can be effected by reaction with reagentssuch as oxalyl chloride or phosphorus trichloride under mild conditions,as described in embodiment (g).

The tricyclic compounds of the general formula I which can be preparedin accordance with the invention are useful as intermediates for themanufacture of corresponding tetracyclic compounds of the steroidseries. The formation of the steroid A-ring can be achieved, forexample, by hydrogenation of the double bond of a compound of thegeneral formula I and subsequent reaction of the hydrogenation productwith, for example, methyl vinyl ketone according to methods which areknown per se.

The starting compounds of formula III, as far as not already known, canbe prepared by methods known per se, for example, by chemical ormicrobiological degra dation of ring D of tetracyclic steroids which aresubstituted accordingly. A compound of formula III with a residue D ofthe formula Ib can be prepared, for example, from disogenin by treatmentwith a culture of Proactinomyces restrictus Turfitt CBS 157.45.

All temperatures in the following Examples are given in degreesCentigrade.

EXAMPLE 1 1.1 g of crude 1-(1,l-ethylenedioxyethyl)-7a-methyl-5-oxo-4-(3-oxopentyl)-hexahydroindane are stirred with a solution of 3 gof'potassium hydroxide in ml of methanol and 10 ml of water for 15 hoursat room temperature. The reaction mixture is poured onto ice water andextracted with ether. The ethereal extract is washed neutral with water.dried and evaporated. Chromatography of the residue on silica gel yieldspure 3( 1.1-ethylenedioxyethyl )-3a.o-dimethyl-7-oxol,2,3,3a.4.5.8,9,9a,9b-decahydro-7H-benz[e]indene.

The indane derivative which is used as the starting material can beprepared as follows:

26.6 g of l-acetyl-4-(2-carboxyethyl)-7a-methyl-5- oxo-hexahydroindaneand 6 g of sodium acetate are dissolved in 400 ml of acetic anhydrideand heated at reflux under nitrogen for 2 hours. The reaction mixture isthen evaporated in vacuum, the residue is twice evaporated with tolueneand dissolved in 1 liter of methyiene chloride. The solution is washedwith water, dried over sodium sulfate and evaporated in vacuum. Theresidue is recrystallized from ether and yields 7-acetyloa-methyl-3(2H)-oxo-l ,6,6a,7,8,9,9a,9b-octahydro- :yclopenta[f][llbenzopyran. 24.8g of the foregoing compound are dissolved in 300 ml of methylenechlotide. The solution is treated with 500 ml of ethylene glycol, 130 mlof orthofonnic acid ethyl ester and 950 mg of p-toluenesulfonic acidmonohydrate and heated to reflux under nitrogen for 3.5 hours. Aftercooling, the reaction mixture is poured onto 3 liters of ice-water whichcontain 420 mg of sodium hydrogen carbonate and extracted with methylenechloride. The organic phase is washed with water, dried over sodiumsulfate and evaporated in vacuum. The residue is dissolved in benzeneand chromatographed on 700 g of silica gel. Elution with hexane/ether(3:1) yields 7-(l,lethylenedioxyethyl)-6a-methyl-3(2H)-oxol,6,6a,7,8,9,9a,9b-octahydro-cyclopenta[f] [llbenzopyran which is recrystallizedfrom ether/isooctane. A solution of ethyl magnesium bromide preparedfrom 545 mg of ethyl bromide in 30 ml of ether is slowly added to asolution of 1.08 g of 7-( 1,1-ethylenedioxyethyl )-6a-methyl-3(2H)-oxol,6,6a,7,8 ,9,9a,9b-octahydro-cyclopenta[f] [l]benzopyran in 50 ml ofether at The solution is held at 0 for hours, then decomposed with 15 mlof saturated ammonium chloride solution. The ethereal solution is washedwith water and dried with sodium sulfate and evaporated in vacuum,yielding crude l-( l ,l-ethylenedioxyethyl)-7amethyl-5 -oxo-4-(3-oxopentyl )-hexahy droindane.

EXAMPLE 2 3-(1-Hydroxyethyl)-3a,6-dimethyl-7-oxol,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e]indeneis obtained from l-( l-acetoxyethyl)-7a-methyl-5-oxo-4-(3-oxopentyl)-hexahydroindane by treatment with aqueous-methanoliccaustic potash in accordance with Example 1.

The indane derivative which is used as the starting material can beprepared as follows:

A solution of 1 g ofl-acetyl-4-(2-carboxyethyl)-7amethyl-S-oxo-hexahydroindane in 100 ml ofisopropanol is treated with 1 g of sodium borohydride and stirred atroom temperature for 3 hours. The reaction mixture is then diluted witha large amount of water, made acidic with hydrochloric acid andextracted with methylene chloride. The organic extract is washed neutralwith water, dried with sodium sulfate and evaporated to dryness invacuum. The residue thus obtained is dissolved in a mixture of 30 ml ofacetic acid anhydride and 30 ml of pyridine. This solution is held atroom temperature for hours and subsequently evaporated to dryness. Forthe removal of excess acetic 10 acid, acetic acid anhydride andpyridine, the residue is repeatedly evaporated with toluene, 1.1 g of7-( 1- acetoxyethyl)-6a-methyl-3-oxo-perhydro-cyclopentalfllllbenzopyran are obtained.

5 g of the foregoing compound are dissolved in 100 ml of dry benzene andtreated under nitrogen with a Grignard solution prepared from 8.8 g ofethyl bromide, 2 g of magnesium and 75 ml of ether. The reaction mixtureis heated to reflux for 18 hours, then treated with dilute hydrochloricacid, washed with water and dried over sodium sulfate. Crystallized fromether-isopropyl ether. the residue yields 3.2 g of 3-ethyl-3-hydroxy-7-(l-hydroxyethyl)-6a-methyl-perhydro-cyclopenta[f][l]benzopyran.

A solution of 2.0 g of the foregoing compound in ml of acetic anhydrideand 30 ml of pyridine is allowed to stand at room temperature for 3hours. The reaction mixture is then poured onto ice-water and extractedwith ether. The ethereal solution is washed with water, dried oversodium sulfate and evaporated. 7( l- Acetoxyethyl)-3-ethyl-3-hydroxy-6a-methyl-perhydrocyclopenta[f][llbenzopyran isobtained which can be used without further purification.

To a solution of 450 mg of the foregoing compound in 20 ml of acetone, asolution of 0.95 g of chromic acid in 6 ml of 2N sulfuric acid is addedduring 10 minutes with stirring at 10. The reaction mixture is thenstirred at 10 for 2 hours, poured onto ice-water and extracted withether. The ethereal solution is washed neutral with water, dried oversodium sulfate and evaporated in vacuum. Recrystallized from ether, theresidue yields l-( l-acetoxyethyl)-7a-methyl-5-oxo-4-( 3-oxopentyl)-hexahydroindane.

Another possibility to prepare the same product is the following:

As described below (see Example 9), the methyl ester of l-acetyl-4-(2-carboxyethyl )-7a-methyl-5-oxohexahydroindane is prepared using anethereal solution of diazomethane. A solution of 14 g of this product in500 ml of benzene is treated with 500 mg of p-toluenesulfonic acidmonohydrate and 30 ml of ethyleneglycol and boiled at thewater-separator with stirring for 60 minutes. After cooling, thereaction mixture is washed with 100 ml of 5 percent sodium hydrogencarbonate solution, then with a total of 300 ml of water and dried oversodium sulfate. After filtration and concentration in water-pump vacuum,1-acetyl-5,5-ethylenedioxy-4-(2-carbomethoxyethyl)-7a-methyl-hexahydroindane is obtained.

A solution of 12 g of this product in ml of methanol is treated underice-cooling within 5 minutes with a total of 4 g of sodium borohydrideand the mixture is stirred at room temperature for a further 60 minutes.It is then concentrated to half in water-pump vacuum and the residue ispoured onto 250 ml of ice-cold 1N hydrochloric acid. The oily fractionsare taken up in either and the extract is concentrated in water-pumpvacuum. The residue is dissolved in 50 ml of dioxane, 100 ml of 2Nhydrochloric acid are added and the mixture is subsequently heated in abath of 80 for 16 hours. The reaction mixture is then concentrated to 40ml in water-pump vacuum, subsequently diluted with ml of water andsubsequently extracted with ether. The organic extract is washed withwater and dried over anhydrous sodium sulfate. After filtration andconcentration of the filtrate in water-pump vacuum, 4-(2-carboxyethyl 11-hydroxyethyl)-7a-methyl-5 -oxo-hexahydroindane remains as the residue.

A solution of 13.4 g of 4-(2-carboxyethyl)-l-(1-hydroxyethyl)-7a-methyl-5-oxo-hexahydroindane and 4 g of sodium acetatein 250 ml of acetic anhydride is boiled at reflux under nitrogen for 4hours. The acetic anhydride is removed in vacuum, the residue twiceevaporated with toluene and finally taken up in 750 ml of methylenechloride. The methylene chloride solution is washed five times withwater, dried over Na SO and evaporated in vacuum. The resulting 7-(l-acetoxyethyl)-6a-methyl-3( 2H )-oxol ,6,6a,7,8,9,9a,9boctahydro-cyclopenta[f][l]benzopyran is directly employed inthe next step.

A solution of 8.8 g of 7-( l-acetoxyethyl)-6a-methyl-3(2l-l)-oxo-1,6,6a,7,8,9,9a,9b-octahydro-cyclopenta[f] [l]benzopyran in250 ml of absolute ether is slowly treated with 60 ml of a 0.5N etherealsolution of ethyl magnesium bromide at 15. After 24 hours. the reactionmixture is poured onto ice-cold saturated ammonium chloride solution.The ethereal solution is washed with water (1 X), ice-cold 0.5N causticpotash (2 X) and again with water (2 X). The organic phase is dried oversodium sulfate, the solvent is removed in vacuum and the residue isfiltered through a column of 25 g of silica gel. 1-(l-Acetoxyethyl)-7a-methyl-5-oxo-4-(3- oxopentyl)-hexahydroindane isobtained as an oil.

EXAMPLE 3 3-Acetyl-3a,6-dimethyl-5-oxol ,2,3 ,3a,4,5,8,9-,9a,9b-decahydro-7H-benz[e]indene is obtained by treatment of1-acetyl-7a-methyl5-oxo-4-(3-oxopentyl)-hexahydroindane withaqueous-methanolic caustic potash in accordance with Example 1.

The indane derivative which is used as starting material can be preparedby oxidation of 3-ethyl-3-hydroxy- 7-(1-hydroxyethyl)-6a-methyl-perhydro-cyclopenta[f][l]benzopyran (preparedas described in Example 2) with chromic acid in analogy to the proceduregiven in Example 2.

EXAMPLE 4 A Grignard solution is prepared from 1.15 g of magnesium, 15ml of ether and g of ethyl bromide. The solution thus obtained isdiluted with 40 ml of ether and treated with 6 g of dry cadmium chlorideunder a nitrogen atmosphere and with stirring. The mixture is thenheated under reflux for 2 hours and, after cooling, filtered undernitrogen atmosphere. To 45 ml of this solution, 690 mg ofl-(l,1-ethylenedioxyethyl)-4-(2-chlorocarbonylethyl)-7a-methyl-S-methylene-hexahydroindane dissolved in25 ml of absolute benzene are added dropwise under nitrogen atmosphere.The reaction mixture is heated under reflux for 2.5 hours, then dilutedwith ice-water and extracted with ether. The ethereal solution is washedwith ammonium chloride solution and water, dried over sodium sulfate andevaporated in vacuum. The residue is chromatographed on 18 g of aluminumoxide (activity grade 111), with hexane/benzene (1:1 to 1:3) pure3-(l,l-ethylenedioxyethyl )-3a-methyl-7-oxo-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e] indene being eluted which isrecrystallized from diisopropyl ether/hexane.

The indane derivative which is used as the starting material can beprepared as follows:

To a suspension of 29.2 g of 7-(1,1-ethylenedioxyethyl )-6a-m ethyl-3(2H )-oxo- 1 ,6,6a,7,8 ,9,9a,9b-octahydro-cyclopentalf][llbenzopyran in100 ml of dioxan are added 220 ml of 0.5N caustic soda. The mixture isstirred until a clear solution has formed, which then is treated withice-cold 1N sulfuric acid under cooling with ice. The precipitate istaken up in 3 liters of methylene chloride. The organic phase is washedwith a saturated aqueous solution of sodium chloride, dried over sodiumsulfate and then evaporated in vacuum. The residue is dissolved in alittle methylene chloride, crystallized from ether and yields l-(l,l-ethylenedioxyethyl)-4-(2-carboxyethyl)-7a-methyl-5-oxo-hexahydroindane.

A solution of 6.2 g of the foregoing compound in ml of methylenechloride and 4 ml of methanol is treated with an ethereal solution ofdiazomethane at 4 up to a persistent yellow colouration of the solution,which then is stirred at room temperature for 45 minutes. Excess ofdiazomethane is removed in vacuum, the solution is diluted with ml ofmethylene chloride, washed with water, dried over sodium sulfate andevaporated to dryness in vacuum. The residue is dissolved inbenzene/ether 15: 1) and filtered over 40 g of aluminum oxide (activitygrade III). Evaporation of the solution to dryness yieldsl-(l,l-ethylenedioxyethyl)- 4-( 2-carbomethoxyethyl)-7a-methyl-S-oxo-hexahydroindane.

A solution of 3.24 g of the compound prepared hereinbefore in 50 ml ofabsolute tetrahydrofuran is added under nitrogen to 20 ml of a 0.75molar solution of methylenetriphenylphosphorane in absolute dimethylsulfoxide. After addition of another 30 ml of tetrahydrofuran thereaction mixture is stirred at 50 for 24 hours, cooled, poured ontoice-water and extracted with ether. The ethereal solution is washed withwater, dried over sodium sulfate and evaporated to dryness in vacuum.The residue is dissolved in a small quantity of ether and treated withabout the 10-fold amount of hexane. The solution thus obtained isfiltered over 25 g of aluminum oxide (activity grade H1). The filtrateis evaporated, taken up in ml of dioxane, treated with 20 ml of 3Ncaustic potash and heated to 70 under nitrogen for 45 minutes. Thesolution is then poured onto ice-water and neutralized with dilutephosphoric acid at 0. The solution is then extracted with chloroform,the chloroform solution washed with a 10% solution of sodium chloride,dried over sodium sulfate, and evaporated in vacuum, yielding 1-(1,1-ethylenedioxyethyl)-4-(2-carboxyethyl)-7a-methyl-5-methylenehexahydroindane.

A solution of 620 mg of the compound prepared hereinbefore in 10 ml ofabsolute benzene are stirred at 3 for an hour with 4.5 ml of freshlydistilled oxalyl chloride. The solvent is then evaporated in vacuum andthe residue dried by repeated evaporation with benzene in vacuum. Theoily l-(1,l-ethylenedioxyethyl)-4-(2-chlorocarbonylethyl)-7a-methyl-5-methylene-hexahydroindane thus obtainedcan be used without further purification.

EXAMPLE 5 3.08 g of 1-(l,1-Ethylenedioxyethyl)-4-(2-carboxyethyl)-7a-methyl-5-methylene-hexahydroindaneprepa ration see Example 4) are dissolved in 50 ml of acetic anhydrideand treated with 50 ml of glacial acetic acid and 800 mg of anhydrouszinc chloride. The reaction mixture is heated under reflux for 4 hourswith vigorous stirring and under a nitrogen atmosphere. The solvent isthen removed in vacuum, the residue dissolved in 100 ml of acetone and,after the addition of 20 ml of 2N sulfuric acid, warmed to 40 for 30minutes. The crude solution is poured onto a large amount of water andthereafter extracted with methylene chloride. The methylene chloridesolution is successively washed 13 with water, sodium carbonate solutionand water, dried over sodium sulfate and evaporated in vacuum. Theresidue is chromatographed on 100 g of silica gel and recrystallizedfrom diisopropyl ether. 3-Acetyl-3amethyl-7-oxol,2,3,3a,4,5,8,9,9a,9b-decahydro-7l-lbenz[e]indene is obtained.

EXAMPLE 6 3.4 g of1-(1,1-Ethylenedioxyethyl)-4-(2-carbomethoxyethyl)-5-ethylidene-7a-methyl-hexahydroindaneare dissolved in 100 ml of glacial acetic acid/boron trifluoride andheated to 90-95 under nitrogen for 2.5 hours. The reaction mixture isthen treated with ml of 2N sulfuric acid and warmed to 50 for minutes.

The cooled solution is poured onto 500 ml of ice water. and extractedwith methylene chloride. The organic phase is washed with 2N causticpotash and subsequently with water, dried over sodium sulfate andevaporated in vacuum. The residue is taken up in 50 ml of benzene andchromatographed on 120 g of silica gel. Elution with benzene/acetone(10:1) yields 3.-a,cetyl-3a,6-dimethyl-7-oxo-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7l-l-ben[e]indenewhich is recrystallized from ether/hexane.

The indane derivative which is used as the starting material can beprepared as follows:

2.5 g of sodium hydride (51% dispersion in mineral oil) are washed withabsolute hexane under nitrogen. After removal of the hexane, 15 ml ofabsolute dimethyl sulfoxide are added and the suspension is heated to 75under nitrogen with stirring for 45 minutes. After cooling to roomtemperature, the solution is treated with a solution of 22.4 g ofethyltriphenylphosphonium iodide in 100 ml of absolute dimethylsulfoxide. To the resulting deep-red solution is added a solution of4.68 g of1-(1,1-ethylenedioxyethyl)-4-(2-carbomethoxyethyl)-7a-methyl-5-oxo-hexahydroindane(prepared by treatment of l-( l,l-ethylenedioxyethyl)- 4-(2-carboxyethyl )-7a-methyl-5-oxo-hexahydroindane, mentioned in Example4, with diazomethane) in 100 ml of absolute dimethyl sulfoxide. Thereaction mixture is warmed to 65 under nitrogen atmosphere overnight.After cooling, it is poured onto ice-water and extracted withether/methylene chloride (4:1). The organic phase is washed with water,dried over sodium sulfate and evaporated in vacuum. The syrupy residueis taken up in petroleum ether/ether 10:1 and chromatographed on 30 g ofaluminum oxide (activity grade I-ll). Elution with petroleum ether/ether10:1 to 6:1) yields oily1-(1,l-ethylenedioxyethyl)-4-(2-carbomethoxyethyl)-5-et.hylidene-7a-methylhexahydroindaneas a mixture of isomers.

EXAMPLE 7 A solution of 3.38 g of l-(1,l-ethylenedioxyethyl)-4-(2-carboxyethyl )-5 -ethylidene-7a-methyl-hexahydroindane in 50 ml ofmethylene chloride is slowly added to ml of 83-85% polyphosphoric acidwhile stirring vigorously. The reaction mixture is warmed to.

and the methylene chloride is slowly drawn off in vacuum. The syrupyresidue is warmed to 55 for 16 hours, then under strong ice-cooling isdiluted with ice-water, treated with 200 ml of acetone and heated to 50for 30 minutes. The reaction mixture is extracted with methylenechloride, the organic solution is worked of ethanol, the solution isheated under reflux for 1 hour and then evaporated until crystallizationbegins. The crystallised disemicarbazone is dissolved in 150 ml ofglacial acetic acid and 50 ml of water, the solution is treated with 13ml of a 1.66N succinic acid solution and warmed to 40 for 3 hours. Afterstanding overnight, the solution is diluted with 3 liters of ether andthe ethereal solution is washed with water, 2N sodium carbonate solutionand water. After drying over sodium sulfate and evaporation, the residueis dissolved in a small quantity of methylene chloride and crystallizedfrom heptane.3-Acetyl-3a,6-dimethyl-7-oxol,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[elindeneis obtained.

The indane derivative used as the starting material can be obtained bytreatment of a solution of the corresponding methyl-ester in dioxanewith 20% aqueous caustic potash. The preparation of the methyl esteritself has already been described in Example 6.

EXAMPLE 8 278 mg of 1-Acetyl-5-ethylidene-4-( 2-carboxyethyl)-7a-methyl-hexahydroindane are dissolved in 5 ml of acetic anhydride. Thesolution is treated with 0.7 ml of concentrated sulfuric acid and heatedunder reflux for 1 hour. After cooling 2 ml of water are added to thesolution, the mixture is stirred at for 1 hour, then cooled, dilutedwith ml of water and extracted with methylene chloride. The organicphase is washed neutral, dried over sodium sulfate and evaporated invacuum. The residue is chromatographed on 5 g of silica gel withbenzene/acetone 10:1), yielding 3-acetyl-3a,6-dimethyl-7-oxo-1,2,3,3a,4,5,8,9,9a,9b-decahy dro-7H-benz[e]indene.

The indane derivative which is used as starting material can be preparedby treatment of l-( 1,1-ethylenedioxyethyl )-5 -ethylidene-4-(2-carboxyethyl )-7a-methylhexahydroindane with 2N sulfuric acid inacetone.

EXAMPLE 9 A solution of 1.39 g of 1-acetyl-7a-methyl-5-oxo-4-(3-oxopentyl)-hexahydroindane in 10 ml of ethanol is treated with 1 mlof pyrrolidine under a nitrogen atmosphere. The solution is stirred at48 for 24 hours, then treated with 40 ml of 2.5N hydrochloric acid andstirred for another 4 hours under nitrogen, diluted with 100 ml of waterand extracted with methylene chloride. The organic phase is washed withhydrochloric acid and subsequently with water, dried over sodium sulfateand evaporated in vacuum. The residue is chromatographed on 30 g ofsilica gel with benzene/acetone (10: 1)3-acetyl-3a,6-dimethyl-7-oxo-1,2,3,3a,4,5,8,9-,9a,9b-decahydro-7H-benz[elindene being eluted which is recrystallizedfrom ether/hexane.

The starting material can be prepared as follows:

a. To a solution of 13.3 g ofl-acetyl-4-(2-carboxyethyl)-7a-methyl-5-oxo-hexahydroindane in 20 ml ofmethylene chloride, 80 ml of 5% ethereal diazomethane solution are addeddropwise within 15 minutes. The mixture is allowed to stand at roomtemperature for 60 minutes, is then treated with 2 ml of glacial aceticacid, 10 minutes later washed with an aqueous solution of sodiumhydrogen carbonate and water, dried over sodium sulfate and evaporated.l-Acetyl-4- (2-carbomethoxyethyl )-7a-methyl-5-oxo-hexahydroindane isobtained.

b. To a solution of 13.3 g of l-acetyl-4-(2-carboxyethyl)-7a-methyl-5-oxo-hexahydroindane in 100 ml of absolutemethanol. 40 g of 10% methanolic hydrochloric acid is added. Thereaction mixture is boiled under reflux for 60 minutes, then isconcentrated in vacuum and the residue taken up in 200 ml of ether. Theethereal solution is washed with a saturated solution of sodium hydrogencarbonate and water, dried and concentrated. l-Acetyl-4-( 2-carbomethoxyethyl 7amethyl-S-oxo-hexahydroindane is obtained.

A solution of 14 g of the ester, the preparation of which is describedhereinbefore, in 600 ml of anhydrous benzene is heated under reflux for30 hours together with 25 ml of ethylene glycol and 1 g ofp-toluenesulfonic acid monohydrate, the water formed being removed in aSoxhlet apparatus by 80 g of calcium carbide. The reaction mixture isthen treated with 3 ml of pyridine and concentrated in water-pumpvacuum. The residue thus obtained is dissolved in 100 ml of dioxanetreated with 50 g of 20% aqueous caustic potash and heated to reflux for2 hours. The reaction mixture is then concentrated in vacuum, theresidue taken up in 100 ml of water, the aqueous solution is treatedwith 9.5 g of glacial acetic acid under ice-cooling, the separating oilis taken up in ether, the ethereal solution is washed with water, driedover magnesium perchlorate and evaporated, yielding 5,5-ethylenedioxyl ll -ethylenedioxyethyl )-4-( 2-carboxyethyl 7a-methyl-hexahydroindane.

To a solution of 355 mg of 5,5-ethylenedioxy-l-( l ,lethylenedioxyethyl)-4-( 2-carboxyethyl )-7a-methylhexahydroindane in 25 ml of methylenechloride, 150 mg of chlorosulfonyl isocyanate in 5 ml of methylenechloride are added at room temperature with stirring and are warmed to40-50 for 30 minutes. After cooling to 15, 0.5 ml of dimethylformamideare added. The reaction mixture is stirred for another 30 minutes, thendiluted with ice-water and extracted with ether/methylene chloride 5:1.The organic phase is washed with 2N caustic potash and thereafterneutral with water, dried over sodium sulfate and evaporated. The oilyresidue is taken up in methylene chloride and chromatographed on 15 g ofsilica gel with benzene/ether. The eluate is concentrated and theresidue dried in high vacuum. 5 ,S-Ethylenedioxyl l l-ethylenedioxyethyl )-4-( 2- cyanoethyl)-7a-methyl-hexahydroindane isobtained.

To a solution of 670 mg of 5,5-ethylenedioxy-l-( 1,1-ethylenedioxyethyl)-4-(2-cyanoethyl)-7a-methyl-hexahydroindane in 40 mlof absolute ether, an ethereal solution of ethyl magnesium iodide(prepared from 2.5 g of magnesium and 7.5 ml of ethyl iodide in 20 ml ofether) is added dropwise within 20 minutes at 10. The reaction mixtureis heated under reflux for 7 hours and then treated with 35 ml ofglacial acetic acid in 25 ml of ether with ice-cooling. The reactionmixture is then concentrated to remove the ether, treated with water,stirred for 2 hours at diluted with a large amount of water andextracted with methylene chloride. The organic phase is washed with asaturated solution of sodium chloride, dried over sodium sulfate andevaporated. 5 ,5-Ethylenedioxyl-( l l-ethylenedioxyethyl)-7a-methyl-4-(3-oxopentyl)-hexahydroindane is obtained. By treatment withp-toluenesulfonic acid in acetone this diketal can be converted intol-acetyl-7amethy1-5-oxo-4-(3-oxopentyl)-hexahydroindane.

EXAMPLE 10 1.75 ml of concentrated hydrochloric acid are added to asolution of 1.23 g of l-acetyl-7a-methyl-5-oxo-4-(3-oxoheptyl)-hexahydroindane in 25 ml of glacial acetic acid, and themixture is stirred under nitrogen at room temperature for 21 hours. Thesolution is then cautiously added to ml of a 5% aqueous solution ofsodium carbonate and stirred for 2 hours with ice-cool ing. Theprecipitate is filtered off, washed with water, and left to dry. lt isthen dissolved in 12 ml of methylene chloride and filtered over 15 g ofsilica gel to give 3-acetyl-3a-methyl-7-oxo-6-propyll ,2,3 ,3a,4,5 ,8,9- ,9a,9b-decahydro-7H-benz[e]indene.

The starting material can be prepared as follows:

36.84 g of5,5-Ethylenedioxy-1-(1,1-ethylenedioxyethyl)-4-(2-carbomethoxyethyl)-7a-methyl-hexahydroindane(obtained by ketalisation in the usual way of l-( l l-ethylenedioxyethyl)-4-(2-carbomethoxyethyl)-7a-methyl-5-oxo-hexahydroindane mentioned already in Example 6) aredissolved in methanol. The solution is treated with 0.8 mole of aqueousconcentrated ammonia, allowed to stand at room temperature for 3 days,and yields on concentration l-(1,1-ethylenedioxyethyl)-5,5-ethylenedioxy-4-(2-carbaminoethyl)-7amethyl-hexahydroindane.

Tetrahydrofuran is added to 34.24 g of this acid amide at 50 under anargon atmosphere until solution takes place. To this solution is addeddropwise a 3- molar solution of butyl magnesium bromide intetrahydrofuran with subsequent stirring at 50 for 24 hours. TheGrignard complex is then decomposed by addition of an ice-cold saturatedsolution of ammonium chloride and the solution is extracted with ether.Working up of the ethereal solution yields5,5-ethylenedioxy-l-(l,lethylenedioxyethyl)-7a-methyl-4-(3-oxoheptyl)-hexahydroindane.This keto-diketal can be converted into the triketone, which isl-acetyl-7a-methyl-5-oxo-4-(3- oxoheptyl)-hexahydroindane, by treatmentwith p-toluenesulfonic acid in acetone.

EXAMPLE 1 1 a. A solution of 4.38 g of 1-acetyl-7a-methyl-5-oxo-4-(3-oxohexyl)-hexahydroindane and 5 g of potassium hydroxide in 50 ml ofethanol and 11 ml of water is stirred at room temperature under nitrogenfor 3 hours. The solution is then diluted with a large amount ofice-water and extracted with ether/methylene chloride (6:1). The organicphase is washed with a saturated aqueous solution of sodium chloride,dried over sodium sulfate and evaporated in vacuum. The residue isdissolved in 20 ml of methylene chloride and chromatographed on 100 g ofsilica gel. At fist the non-polar byproducts are eluted withhexane/methylene chloride, later on there is eluted3-acetyl-6-ethyl-3a-methyl-7-oxo-l,2,3,3a,4,5,8,9,9a,9b-decahydro-71-1-benz[e]indene with methylenechloride/ether (8:1) which compound is recrystallized from methylenechloride/diisopropyl ether with the addition of a small quantity ofpentane.

b. To a solution of 2.92 g of l-acetyl-7a-methyl-5-oxo-4-(3-oxobutyl)-hexahydroindane in 250 ml of absolute benzene isadded mg of p-toluenesulfonic acid monohydrate. The reaction mixture isheated to boiling under an argon atmosphere then subjected to azeotropicdistillation, at first 60 ml of benzene being distilled off and thebenzene distilling off in the course of the further distillation beingreplaced by dropwise addition of fresh benzene. After 3 hours, thereaction mixture is cooled, poured onto an ice-cold 4% aqueous solutionof sodium hydrogen carbonate and extracted with ether. The etherealphase is washed with water, dried over sodium sulfate and evaporated invacuum.

17 Working up in accordance with the process described in paragraph (a)yields3-acetyl-3a-methyl-7-oxol,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benzlel-indene.

The starting material for (a) can be prepared as follows:

To a solution of 3.54 g of 5,5-ethylenedioxy-1-(1.1- ethylenedioxyethyl)-4-( 2-carboxyethyl )-7a-methylhexahydroindane (preparation see Example9) in absolute benzene is added 0.6 ml of phosphorus trichloride at 6.The mixture is allowed to stand at this temperature under nitrogen for 3hours. Then the benzene solution is separated from phosphorusoxychloride by decantation and evaporated to dryness in vacuum. Theresidue is evaporated again with another 25 ml of benzene and the oily5,5-ethylenedioxy-l-( l,'l-ethylenedioxyethyl )-4-(2-chlorocarbonylethyl )-7a-methyl-hexahydroindane is dried in highvacuum.

An ethereal solution of 3.73 g of 5,5-ethylenedioxyl-( l,l-ethylenedioxyethyl )-4-( 2-chlorocarbonylethyl7a-methylhexahydroindane is added to a solution of 430 mg ofethyleneimine and 1.01 g of triethylamine in 20 ml of absolute etherunder a nitrogen atmosphere. The solution is stirred at for 2 hours,filtered off from triethylammonium hydrochloride which separates out andto the filtrate is added an ethereal solution of 380 mg of lithiumaluminum hydride under nitrogen. The solution is stirred at 5 for 2hours, cooled to 20 and treated with 1.3 ml of a saturated solution ofsodium sulfate. The solution is allowed to warm slowly and is finallyheated under reflux for 30 minutes. The precipitate is filtered off andwashed with methylene chloride. The filtrate and the methylene chlorideliquors are combined, washed with water, dried over sodium sulfate andevaporated. The oily residue is dissolved in benzene and a smallquantity of methylene chloride and filtered over 20 g of silica gel.Concentration of the filtrate yields 5,5-ethylenedioxyl 1 1-ethylenedioxyethyl )-4-( 2-formylethyl )-7a-methyl-hexahydroindane.

A solution of 440 mg of n-propyl magnesium bromide in 10 ml of absoluteether is added with good stirring at 20 to a solution of 746 mg of5,5-ethylenedioxyl 1 l-ethylenedioxyethyl )-4-( 2-formylethyl)-7a-methyl-hexahydroindane in 20 ml of absolute tetrahydrofuran. After 1hour, the cooling bath is removed and the temperature is allowed to riseto Th'ereaction mixture is poured into ice-cold ammonium chloridesolution and extracted with methylene chloride. The organic phase iswashed with 2N caustic potash and water, dried over sodium sulfate andevaporated to dryness in vacuum. The oily residue is dissolved in 30 mlof acetone, treated with 2 ml of 2N sulfuric acid and heated to 45 for30 minutes. After dilution with 500 ml of water, the mixture isextracted with methylene chloride, the organic phase is washed with 1Ncaustic potash and water, dried and evaporated in vacuum. The oilyresidue is chromatographed on 35 g of aluminum oxide (activity 111).Oily 7-acetyl-4a-hydroxy-6a-methyl-3-propylperhydro-cyclopenta[f][ 1]benzopyran is eluted with hexane/ether (2:1 and 1:1 and pure ether.

Within minutes a solution of 816 mg of chromic acid in 5 ml of 6Nsulfuric acid is added to a solution of 480 mg of7-acetyl-4a-hydroxy-6a-methyl-3-propylperhydro-cyclopenta[f][ l]benzopyran in 10 ml of acetone with stirring at 20.

The solution is stirred at 20 for 3 hours, then treated with 1 ml ofethanol and poured into 150 ml of water. The reaction mixture isextracted with methylene chlo- 18 ride, the organic phase is washed withwater, dried over sodium sulfate and evaporated to dryness in vacuum.The residue is chromatographed on 24 g of silica gel,1-acetyl-7a-methyl-5-oxo-4-( 3-oxohexyl )-hexahydroindane being elutedwith hexane/diisopropyl ether (1:1 and 1:2).

The same product can also be prepared in the following manner:

2.25 ml of a 1.35 molar solution of aluminum diisobutyl hydride is addeddropwise to a solution of 1 g of 5,5-ethylenedioxyl l l-ethylenedioxyethyl )-4-( 2- cyanoethyl)-7a-methyl-hexahydroindane.(Obtained from 5 ,S-ethylenedioxyl 1 1 -ethylenedioxyethyl )-4-(2-carboxyethyl)-7a-methylhexahydroindane as is described in Example 9)in n-heptane under nitrogen atmosphere at l0. After 5 minutes, there areadded dropwise 0.3 ml of a saturated sodium sulfate solution and then 15g of solid sodium sulfate. After addition of ml of methylene chloridethe mixture is stirred for 60 minutes and filtered, the filter cakebeing washed with methylene chloride. The filtrate and the wash-liquidare combined and evaporated to dryness. The oily residue is dissolved ina small quantity of ethanol, treated with saturated aqueous sodiumsulfate solution and stirred at 15 for 25 minutes. The reaction mixtureis cooled and filtered. The precipitate is shaken with 50 ml of 10%caustic soda and extracted with ether. The ethereal solution is washedwith a saturated aqueous solution of sodium chloride, dried over sodiumsulfate and evaporated in vacuum, yielding 5,5-ethylenedioxyl-( 1,1-ethylenedioxyethyl)-4-(2-formylethyl)-7amethyl-hexahydroindane.

EXAMPLE 12 1-Acetyl-7a-methyl-5-oxo-4-(3-oxobutyl)-hexahydroindane istreated with aqueous ethanolic caustic potash in accordance with Example11 paragraph a) yielding 3-acetyl-3a-methyl-7-oxo-l,2,3,3a,4,5,8,9-,9a,9b-decahydro-7l-l-benz[el-indene.

The starting material can be prepared as follows:

a. To 34.24 g of 5,5-ethylenedioxy-l-( 1,1-ethylenedioxyethyl )-4-(Z-carbaminoethyl )-7a-methyl-hexahydroindane (see Example 10)tetrahydrofuran is added at 50 under an argon atmosphere until solutiontakes place. To this solution there is added dropwise a 3- molarsolution of methyl magnesium bromide in tetrahydrofuran. The mixture isthen stirred at 50 for 24 hours. The Grignard complex is decomposed byaddition of an ice-cooled saturated aqueous solution of ammoniumchloride and the reaction product is extracted with ether.

Working up of the ethereal solution yields 5,5-ethylenedioxy-( 1 l-ethylenedioxyethyl )-7a-methyl-4-( 3- oxobutyl)-hexahydroindane. Theanalogous reaction with ethyl magnesium bromide leads to a homologouscompound.

35.24 g of 5,5-ethylenedioxy-1-(1,1-ethylenedioxyethyl )-7a-methyl-4-(3-oxobutyl )-hexahydroindane are treated with acetone until solutiontakes place. To this solution such an amount of water is added as ispossible Without causing turbidity. Then 1.5 g of p-toluenesulfonic acidmonohydrate are added and the reaction mixture is stirred at roomtemperature until no more diketal is detectable on the thin layerchromatogram. The reaction mixture is neutralized with a saturatedsolution of sodium bicarbonate and treated dropwise with 1 liter ofwater, yielding l-acetyl-7a-methyl-5-oxo- 19 4-(3oxobutyl)-hexahydroindane as a precipitate which can be recrystallizedfrom ether/hexane.

b. To 20 ml of a l-molar ethereral solution of cadmiumdimethyl asolution of 750 mg of 5,5-ethylenedioxyl-(l,1-ethylenedioxyethyl)-4-(2-chlorocarbonylethyl)- 7a-methylhexahydroindane (see Example 11) in 25 ml of absolute benzene isadded and the mixture heated under reflux for 2 hours. After cooling,the solution is poured onto 500 ml of ice-water and extracted withether/methylene chloride (4:1). The organic phase is washed with water,dried over sodium sulfate and evaporated in vacuum. The5,5-ethylenedioxy-l-( l ,lethylenedioxyethyl )-7a-methyl-4-( 3-oxobutyl)-hexahydroindane which is thus obtained is further reacted as describedin paragraph a).

c. To a solution of 1.4 g of methyl-lithium in 50 ml of absolute ether asolution of 10.5 g of 5,5-ethylenedioxyl1,1ethylenedioxyethy1)-4-(2-carboxyethyl)- 7a-methylhexahydroindane in300 ml of absolute ether is added within 25 minutes under nitrogenatmosphere. The mixture is stirred for a further 20 minutes, then pouredonto ice and the organic phase separated. After washing with a total of500 ml of water, the ethereal solution is dried over anhydrous sodiumsulfate. Filtration and concentration in a water-pump vacuum yields,5-ethylenedioxy- 11,1-ethylenedioxyethyl)-7amethy1-4-(3-oxobuty1)-hexahydroindane which isfurther reacted as described under (a).

EXAMPLE 13 A solution of 18.8 g ofdesA-9,10-seco-25D-spirostane-5,9-dione and 16.8 g of potassiumhydroxide in 200 m1 of rectified spirit and 45 ml of water is stirred atroom temperature under nitrogen atmosphere for 3 hours. The reactionsolution is then poured onto 2 liters of ice-water and extracted with 2liters of methylene chloride. The organic phase is washed with saturatedaqueous sodium chloride solution, dried over sodium sulfate andevaporated in vacuum. The residue is chromatographed on 600 g ofSilicagel. Elution with benzene/cyclohexane/ether (lOzlOzl) yieldsdesA-ZSD- spirost-9-en-5-one which is recrystallized fromacetone/hexane.

The starting material can be prepared as follows:

A mixture of 400 ml of acetic ester, 0.5 ml of 72% perchloric acid and48 ml of acetic anhydride is made up to 500 ml with acetic ester. 400 mlof this solution are stirred under nitrogen at room temperature for 25minutes with 7.28 g of desA-19-nor-5,9-seco-25D-spirostan-9-one-5-carboxylic acid and then poured into 300 ml of a coldsaturated aqueous solution of sodium hydrogen carbonate. The aceticester layer is separated, washed with water, dried over sodium sulfateand concentrated in vacuum. The residue is treated with benzene andagain evaporated to dryness in vacuum. The residue is dissolved inbenzene/ether and filtered over 80 g of silica gel. Concentration of thesolution yields desA-19-nor-l0-oxa-25D-spirost-9( l 1 en-5-one which isfurther used without purification.

55 ml of a 2 molar ethereal solution of ethyl magnesium bromide aretreated dropwise at and under stirring with a solution of 34.6 g of thecompound prepared as described above in 250 ml of tetrahydrofuran. Thereaction mixture is stirred at 50 to 60 under nitrogen for 2.5 hours andthen is slowly warmed to 0. The solution is then poured onto an ice-coldsaturated ammonium chloride solution and treated with 1.75 liters ofether. The organic phase is separated, washed with a cold aqueoussolution of sodium hydrogen sulfate and water, dried over sodium sulfateand evaporated in vacuum. The residue is dissolved in methylene chlorideand filtered over 35 g of silicagel. The oilydesA-9,10-seco-25D-spirostane-5,9-dione obtained on evaporation of thefiltrate is employed for the cyclisation without further purification.

We claim: 1. A compound of the general formula 0 I CH R d cu 2 wherein Xis a C alkylidene group; R is hydroxy, lower alkoxy or halogen and R151,1-ethylenedioxyethyl.

2. The compound of claim 1 which is 1-(l,1-ethylenedioxyethyl)-4-(2-carboxyethyl)-7a-methyl-5-methylene-hexahydroindane.

3. The compound of claim 1 which is 1-(1,1-ethylenedioxyethyl)-4-(2-chloro-carbonylethyl)-7amethyl-5-methylene-hexahydroindane 4. The compound of claim 1which is l-(l, lethylenedioxyethyl)-4-( 2-carbomethoxyethyl )-5-ethylidene-7a-methyl-hexahydroindane.

5. The compound of claim 1 which is 1-(1,1-ethylenedioxyethyl)-4-(2-chlorocarbonylethyl)-5-ethylidene-7a-methyl-hexahydroindane.

1. A COMPOUND OF THE GENERAL FORMULA
 2. The compound of claim 1 which is1-(1,1-ethylenedioxyethyl)-4-(2-carboxyethyl)-7a-methyl-5-methylene-hexahydroindane.
 3. The compound of claim 1 which is1-(1,1-ethylenedioxyethyl)-4-(2-chloro-carbonylethyl)-7a-methyl-5-methylene-hexahydroindane.
 4. The compound of claim 1which is1-(1,1-ethylenedioxyethyl)-4-(2-carbomethoxyethyl)-5-ethylidene-7a-methyl-hexahydroindane.
 5. The compound of claim 1 which is1-(1,1-ethylenedioxyethyl)-4-(2-chlorocarbonylethyl)-5-ethylidene-7a-methyl-hexahydroindane.